Both stroma and stem cell factor maintain long-term growth of ELM erythroleukemia cells, but only stroma prevents erythroid differentiation in response to erythropoietin and interleukin-3.
Defining how the stromal requirements of hematopoietic progenitors change during leukemia progression is an important topic that is not well understood at present. The murine ELM erythroleukemia is an interesting model because the erythroid progenitors retain dependence on bone marrow-derived stromal cells for long-term growth in vitro, and they also undergo erythroid differentiation in the presence of erythropoietin (EPO) and interleukin-3 (IL-3). In this report, we have shown using neutralizing antibodies that stem cell factor (SCF), insulin-like growth factor (IGF)-1, and integrin signaling pathways are all involved. We then determined whether ELM cells can be maintained long-term without stroma in various combinations of growth factors produced by stroma cells or growth factors for which ELM cells have receptors. This showed that ELM cells could be maintained with high efficiency in SCF alone; furthermore, the cells remained absolutely SCF-dependent and did not become more tumorigenic than cells maintained on stroma. In contrast, ELM cells underwent clonal extinction when serially cloned in IGF1; any cells that survived long-term growth in IGF-1 were found to be IGF1-independent. One important difference between maintaining ELM cells on stroma and growth in SCF is that stroma reversibly inhibits their differentiation in response to EPO and IL-3, whereas SCF does not.
O'Prey
J
J
Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow G61 1BD, Scotland.
Leslie
N
N
Itoh
K
K
Ostertag
W
W
Bartholomew
C
C
Harrison
P R
PR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D003470:Culture Media; D004921:Erythropoietin / Q000494:pharmacology*; D005109:Extracellular Matrix; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D016023:Integrins / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D051379:Mice; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology*; D017154:Stromal Cells / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D003470:Culture Media; D007328:Insulin; D016023:Integrins; D007377:Interleukin-3; D019089:Stem Cell Factor; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II